The number of pregnant women using methamphetamine (MA) is increasing. Exposure to MA in utero leads to neurological and cognitive deficits in infants that persist into adulthood. Yet, the neurobiology underlying these deficits is not known. Understanding the neurobiological mechanisms behind MA-induced neurological and cognitive impairments will advance our understanding of MA's actions in the brain and offer insights into developing therapies for children exposed to MA in utero. MA administration in adults impairs the cholinergic system. However, little is known about the effects of fetal MA exposure on cholinergic function. One of NIDA's goals is to improve treatment for drug abuse and the objective of this project is in line with this goal, as the objective is to explore the long-term effects of in utero MA exposure on the cholinergic system and to investigate potential cholinergic therapies that may reverse MA-induced cognitive deficits in adulthood. This objective will be achieved by administering MA to mice during hippocampal development, which occurs during the first 3 postnatal weeks and mimics human hippocampal development during the third trimester. The specific aims of this proposal are: 1) determine the effects of neonatal MA on choline acetyltransferase positive cells in the basal forebrain and fiber densities innervating the hippocampus and cortex in adulthood. This will be achieved using immunohistochemistry and confocal microscopy with densitometry and unbiased stereological techniques;2) determine the effects of neonatal MA on the number and affinity of M1 and M2 muscarinic receptors in the hippocampus and cortex in adulthood using muscarinic acetylcholine receptor binding assays;and 3) determine the ability of the acetylcholinesterase inhibitor rivastigmine or the muscarinic receptor agonist carbachol, injected directly into the lateral ventricle, to reverse cognitive impairments resulting from neonatal MA in adulthood. PUBLIC HEALTH RELEVANCE: As children exposed to MA in utero display impairments on a variety of cognitive tasks, it is imperative that the underlying neurobiology of these impairments is delineated and that treatments for these children are developed. Thus, this proposal will impact public health by increasing the possibility that these treatments will be discovered. The number of children exposed to MA in utero is increasing. Exposure to MA in utero leads to long-term cognitive and behavioral problems in children that affect our school systems and our society. This proposal will investigate the changes in neurobiology that result from in utero MA exposure and explore potential therapies to treat children that have cognitive impairments as a result of in utero MA exposure.